Marijuana is the most commonly used illegal drug of abuse in the United States. Chronic use of marijuana produces tolerance or dependence, and cannabis-related disorders. These effects are mainly mediated by ?9-tetrahydrocannabinol (?9-THC), the major psychoactive constituent in marijuana, which activates cannabinoid receptors in the CNS. However, the mechanisms by which ?9-THC alters synaptic function and develops tolerance are largely unknown. Accumulated information suggests that astroglial cells, an important element of tripartite synapses, actively participate in neuronal synaptic transmission and plasticity. The presence of bidirectional communication between astroglial cells and neurons suggests that alterations in astroglial behaviors by abused drugs may influence neuronal synaptic transmission and neuroadaptation and produce tolerance and addiction. Indeed, astroglial cells express cannabinoid receptors, which are targets of ?9-THC. It has been shown that ?9-THC exposure during development significantly decreases expression of glutamate transporters in cerebellar astroglial cells, indicating that glutamate uptake is reduced in astroglial cells exposed to ?9-THC. In our preliminary studies, we observed that chronic exposure to ?9-THC significantly attenuated hippocampal long-term potentiation (LTP) and reduced expression of the glutamate receptor. We also found that astroglial cells are able to undergo plasticity in response to presynaptic high-frequency stimulation. The plasticity of astroglial-neuronal synapses may be an important and integrated component of neuronal synaptic plasticity. Thus, we hypothesize that ?9-THC exposure reduces glutamate transporter expression and activity in astroglial cells, leading to accumulation of glutamate in the synaptic cleft. This results in functional desensitization and down-regulation of the glutamate receptors on both neurons and astroglial cells, which contributes to the ?9-THC exposure-altered synaptic plasticity. To test this hypothesis, we will accomplish the following two specific aims: 1) To test the hypothesis that chronic exposure to ?9-THC reduces hippocampal glutamate transporter expression and activity in astroglial cells; 2) To test the hypothesis that chronic exposure to ?9-THC reduces hippocampal glutamate receptor expression and function on both neurons and astroglial cells, resulting in impairments in synaptic plasticity. PUBLIC HEALTH RELEVANCE: The proposed research will provide important information on the involvement of astroglial cells in marijuana-induced neuroadaptive changes in synaptic circuits, and is expected to further our understanding of the molecular and cellular mechanisms underlying marijuana abuse-induced tolerance and alterations in synaptic plasticity and cognitive function. [unreadable] [unreadable] [unreadable]